Intra-arterial ACNU therapy for malignant brain tumors

1983 ◽  
Vol 59 (3) ◽  
pp. 424-430 ◽  
Author(s):  
Junkoh Yamashita ◽  
Hajime Handa ◽  
Yasuhiko Tokuriki ◽  
Young Soo Ha ◽  
Shin-Ichi Otsuka ◽  
...  
Keyword(s):  
Survival Time ◽  
Postoperative Radiotherapy ◽  
Glioma Cells ◽  
Mantel Test ◽  
Survival Times ◽  
Content Type ◽  
The Difference ◽  
Intracarotid Administration ◽  
Fine Print

✓ The authors examined the growth rate of mouse 203 glioma cells in vitro and found it to be markedly inhibited after exposure to ACNU for 5 minutes at a drug concentration of 100 µg/ml. Rats that had undergone intracranial implantation of T1 neurogenic tumor were treated by 5 mg/kg of ACNU administered either intravenously or intra-arterially. The median survival times for the control animals and the animals undergoing intravenous or intracarotid administration of ACNU were 23, 29, and 46 days, respectively. The difference in survival time between the intravenous and intracarotid administration groups was statistically significant (p < 0.01) when examined by the Cox-Mantel test. In a clinical trial, 17 patients with glioblastoma were treated by ACNU, eight intravenously and nine by the intra-arterial route. The drug was given in doses of 2 to 3 mg/kg at least twice before and twice after a course of postoperative radiotherapy. Intra-arterial administration was performed over a period of 5 minutes under local anesthesia. The median postoperative survival time for the patients in the intra-arterial group was 12.5 months, compared with 9.0 months for those in the intravenous group. The survival rate for the intra-arterial group was slightly higher, although statistically not significant, probably because the number of cases was small. The degree of thrombocytopenia due to ACNU tended to be less marked in the intra-arterially treated patients. The theoretical advantages of the intra-arterial administration of ACNU are discussed.

Inhibitory effect of antisense epidermal growth factor receptor RNA on the proliferation of rat C6 glioma cells in vitro and in vivo

2000 ◽  
Vol 92 (1) ◽  
pp. 132-139 ◽  
Author(s):  
Peiyu Pu ◽  
Xuwen Liu ◽  
Aixue Liu ◽  
Jianling Cui ◽  
Yunting Zhang
Keyword(s):  
Survival Time ◽  
Glioma Cells ◽  
C6 Glioma ◽  
C6 Glioma Cells ◽  
C6 Cells ◽  
Content Type ◽  
Proliferation Activity ◽  
Fine Print

Object. The goal of this study was to evaluate the effect of antisense epidermal growth factor receptor (EGFR) RNA on the growth of rat glioma cells in vitro and in vivo and to determine the feasibility of targeting the EGFR gene for gene therapy in gliomas.Methods. Antisense EGFR complementary (c)DNA was transfected into C6 glioma cells by using lipofectamine. In vitro studies, Southern and Northern blot analyses, in situ hybridization, and immunohistochemical staining were designed to examine the integration and expression of antisense EGFR constructs. The 3′(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide (MTT) assay and the average number of argyrophilic nuclear organizer regions (Ag-NORs) were used to evaluate cell proliferation, whereas the terminal deoxynucleotidyl transferase—mediated deoxyuridine triphosphate nick-end labeling (TUNEL) method and microscopy were used to observe cell apoptosis. As part of the in vivo studies, parental C6 cells and C6 cells transfected with EGFR antisense cDNA were implanted stereotactically into the right caudate nucleus of Wistar rats (C6-injected animals and transfected C6-injected animals). Rats with well-established cerebral C6 glioma foci were treated intratumorally with either antisense EGFR cDNA or empty-vector DNA by using lipofectamine (treated-C6 and control treated group). The general behavior and survival of the rats, findings on magnetic resonance images of their brains, histopathological changes, proliferation activity, and apoptosis of the cerebral gliomas in each group of rats were examined.Exogenous antisense EGFR cDNA was integrated into the genome of C6 cells and expressed. In clones with a high expression of the antisense construct, there was a dramatic decrease in endogenous EGFR messenger RNA and protein levels, reduced proliferation activity, and induction of apoptosis in vitro. The mean survival time of rats injected with C6 cells was 17.3 days. The mean survival time of rats injected with C6 cells followed by treatment with empty vector in lipofectamine was 15.4 days. Survival time was significantly prolonged in 100% of the rats injected with antisense-transfected C6 cells and in two thirds of the rats injected with C6 cells followed by antisense EGFR cDNA. Magnetic resonance imaging revealed distinct cerebral tumor foci in C6-injected rats and in control rats of the treated group, but none were found in the rats injected with transfected C6 cells. Furthermore, tumor foci disappeared completely in C6-injected rats treated with antisense EGFR cDNA. The cerebral gliomas of the rats treated by injection of antisense EGFR RNA were characterized by reduced proliferation activity and the induction of apoptosis.Conclusions. The results of this study indicate that EGFR plays an important role in the genesis of malignant gliomas. It may, therefore, be an effective target of antisense gene therapy in patients with gliomas.

Combined cyclotron fast-neutron and BCNU therapy in a rat brain-tumor model

1981 ◽  
Vol 54 (4) ◽  
pp. 461-467 ◽  
Author(s):  
Alexander M. Spence ◽  
Joseph P. Geraci
Keyword(s):  
Gamma Irradiation ◽  
Survival Time ◽  
Fast Neutron ◽  
Combined Therapy ◽  
Tumor Model ◽  
Survival Times ◽  
Gamma Photon ◽  
Maximum Enhancement ◽  
Content Type ◽  
Fine Print

✓ The combination of cyclotron fast-neutron radiotherapy with BCNU chemotherapy was compared to 137Cs gamma photon radiotherapy combined with BCNU in the 36B-10, F-344 rat-transplanted glioma model. Radiation and drug treatments were administered 7 to 8 days after intracerebral tumor implantation. Increase in animal survival time was used as the measure of the effectiveness of various treatment schedules. Single-dose neutron or gamma radiotherapy was tested on Day 7 over the ranges 0 to 900 rads and 0 to 2000 rads, respectively. This therapy produced increases in mean survival times up to 70% at the highest radiation doses. When BCNU (10 mg/kg body weight) was administered intravenously on Day 8, 1 day following radiotherapy, mean survival times were increased by an additional 35% to 50%, irrespective of the dose or type of irradiation. In contrast, by using the same radiation and drug doses but scheduling combined therapy trials so that BCNU was administered 1 hour before either neutron or gamma irradiation on Day 7, there was enhancement of the radiation effect by BCNU. Under these conditions, the maximum enhancement of the mean survival time was 70% to 75% in neutron-treated animals and 120% to 150% in gamma-treated animals. Treatment with BCNU 1 hour before or 1 day after neutron irradiation proved to be no more effective in improving the survival time of tumor-bearing animals than the drug similarly combined with conventional gamma irradiation.

In vitro photoradiation therapy of the rat 9L gliosarcoma

1986 ◽  
Vol 64 (5) ◽  
pp. 775-779 ◽  
Author(s):  
Douglas Hamilton ◽  
John D. S. McKean ◽  
John Tulip ◽  
Donald Boisvert ◽  
Judy Cummins
Keyword(s):  
Trypan Blue ◽  
Glioma Cells ◽  
Laser Source ◽  
Trypan Blue Exclusion ◽  
Content Type ◽  
9L Gliosarcoma ◽  
Trypan Blue Exclusion Test ◽  
9L Glioma ◽  
Fine Print

✓ The authors have investigated various factors involved in the photoradiation treatment of 9L glioma cells. The cells were grown in tissue culture and exposed to light from a laser source that allowed accurate quantitation of the light energy. Cell death was determined following treatment using the trypan blue exclusion test. It was shown that the treatment is very wavelength-dependent following the absorption spectrum of hematoporphyrin derivative (HPD). The absorption peaks in the lower part of the spectrum are more efficient than those of higher wavelengths. Photoradiation therapy is more effective the higher the concentration of HPD. Intensity of light is a very important factor in calculating the total dose of light necessary for this treatment.

Vascular endothelial growth factor expression and vascular density as prognostic markers of survival in patients with low-grade astrocytoma

1998 ◽  
Vol 88 (3) ◽  
pp. 513-520 ◽  
Author(s):  
Saleem I. Abdulrauf ◽  
Klaus Edvardsen ◽  
Khang L. Ho ◽  
Xiao Yi Yang ◽  
Jack P. Rock ◽  
...  
Keyword(s):  
Growth Factor ◽  
Survival Time ◽  
Malignant Transformation ◽  
Median Survival ◽  
Median Survival Time ◽  
Tumor Tissue ◽  
Low Grade ◽  
Survival Times ◽  
Content Type ◽  
Fine Print

It has long been recognized that some patients with low-grade astrocytoma may survive for many years, whereas in others the disease follows a more malignant course resulting in a short survival time, usually due to malignant transformation into higher-grade tumors. Object. The aim of this study was to investigate angiogenesis in the initial biopsy specimen of tumor tissue as a biological marker to identify patients with low-grade astrocytoma who are at high risk of malignant tumor transformation or death. Methods. Tumor tissue was studied in 74 consecutively treated adult patients in whom a diagnosis of diffuse supratentorial hemispheric histologically proven fibrillary low-grade astrocytoma was made and who underwent surgery between January 1972 and January 1994. Studies were conducted using monoclonal antibodies to the antigens of the proliferation-associated Ki-67 (MIB-1), factor VIII, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and epidermal growth factor (EGF). The overall 5-year survival rate for the entire patient population was 65%, with a median survival time of 7.5 years. The total mean follow-up period was 6.1 years. All tumors showed a low proliferative potential at the time of the initial operation, as demonstrated by an MIB-1 labeling index of less than 1.5%. Patients with more than seven microvessels in tumor tissue (29 cases) had a shorter survival time (mean 3.8 years) than those with seven or fewer microvessels (mean survival 11.2 years). This difference in survival times was significant by univariate (p = 0.001) and stepwise multivariate analyses (p < 0.001). Tumors with a larger number of microvessels also had a greater chance of undergoing malignant transformation (p = 0.001). Similarly, significant staining for VEGF was correlated with shorter survival times when using univariate (p = 0.003) and multivariate (p = 0.008) analyses and with a greater chance of malignant transformation (p = 0.002). Patients with tumors staining positive for VEGF (39 individuals) had a median survival time of 5.3 years, and those with tumors negative for VEGF (35 patients) had a median survival time of 11.2 years. No association was observed between bFGF, EGF, and survival or malignant transformation. The stepwise multivariate analysis included histological and clinical variables simultaneously. Conclusions. The authors have shown that microvessel density and VEGF levels are independent prognostic markers of survival in fibrillary low-grade astrocytoma. This finding leads them to propose that fibrillary diffuse low-grade astrocytoma is not a single pathological entity but is composed of a spectrum of tumors with differing propensities to undergo malignant transformation that is at least partly based on their inherent angiogenic potential.

Antiproliferative effect of trapidil, a platelet-derived growth factor antagonist, on a glioma cell line in vitro

1990 ◽  
Vol 73 (3) ◽  
pp. 436-440 ◽  
Author(s):  
Jun-ichi Kuratsu ◽  
Yukitaka Ushio
Keyword(s):  
Growth Factor ◽  
Cell Lines ◽  
Glioma Cell ◽  
Glioma Cells ◽  
Inhibitory Effect ◽  
Platelet Derived Growth Factor ◽  
Content Type ◽  
Glioma Cell Lines ◽  
Fine Print

✓ Platelet-derived growth factor (PDGF) is produced by glioma cells. However, there is heterogeneity among glioma cell lines in the production of PDGF. It has been demonstrated that U251MG cells produce a PDGF-like molecule while U105MG cells do not. Trapidil, a specific antagonist of PDGF, competes for receptor binding with PDGF. Therefore, the inhibitory effect of trapidil on the proliferation of glioma cells was investigated in vitro using two glioma cell lines. At 100 µg/ml, trapidil significantly inhibited the proliferation of U251MG cells (which produce the PDGF-like molecule). At the same trapidil concentration, the proliferation of U105MG cells (which do not produce the PDGF-like molecule) was not inhibited. The inhibitory effect of trapidil was remarkable on Days 3 and 4 of culture. After 4 days of incubation, the proliferation of U251MG cells was 46% of the control preparation. Trapidil enhanced the antitumor effect of 3-((4-amino-2-methyl-5-pyrimidinyl)ethyl)-1-(2-chloroethyl)-1-nitro-sourea (ACNU) against U251MG cells. The enhancing effect was highest on Days 4 and 6 of culture. After 6 days of incubation in the presence of 100 µg/ml trapidil and 1 µg/ml ACNU, the proliferation of U251MG cells was 18% of the control preparation. These findings suggest that trapidil interrupts the autocrine loop at the PDGF and PDGF-receptor level and that combination therapy with trapidil and ACNU may be useful in the treatment of glioma.

Modulation of phorbol ester—induced regulation of matrix metalloproteinases and tissue inhibitors of metalloproteinases by SB203580, a specific inhibitor of p38 mitogen-activated protein kinase

2002 ◽  
Vol 97 (1) ◽  
pp. 112-118 ◽  
Author(s):  
Myung-Jin Park ◽  
In-Chul Park ◽  
Jin-Heang Hur ◽  
Mi-Suk Kim ◽  
Hyung-Chan Lee ◽  
...  
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Specific Inhibitor ◽  
Glioma Cells ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Boyden Chamber ◽  
Content Type ◽  
In Vitro Invasion ◽  
Fine Print

Object. Expression of matrix metalloproteinases (MMPs) has been postulated to play a central role in brain tumor invasion; however, its underlying mechanism is not yet fully understood. In the present study, by assessing the effect of a specific p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, on the secretion of MMPs and in vitro invasion of various glioma cells, the authors attempt to define the role of the p38 MAPK pathway in the regulation of MMPs and tissue inhibitors of metalloproteinases (TIMPs) activated by phorbol ester (phorbol-12-myristate-13-acetate [PMA]) in the D54 human glioblastoma cell line. Methods. The activation of MAPKs was determined using Western blot analysis after addition of phospho-specific antibodies against these kinases, the status of MMPs and TIMPs was analyzed using gelatin zymography and Western blot analysis, and the invasion rate of D54 cells and other glioma cells was analyzed using a modified Boyden chamber assay. Treatment of D54 cells with PMA activated two distinct MAPKs, extracellular signal-regulated kinase (ERK) 1/2 and p38 MAPK, but not c-Jun N-terminal kinase/stress-activated protein kinase. Induction of MMP-9 production and MMP-2 activation by PMA were blocked by SB203580, a specific inhibitor of p38 MAPK, but not by PD98059, a specific inhibitor of ERK 1/2. In addition, PMA-induced downregulation of TIMP-1 and TIMP-2 secretion and upregulation of the membrane type 1 MMP, a major activator of MMP-2 on the cell surface, were reversed by SB203580 in these cells; the PMA-induced increase of invasion in vitro decreased when SB203580 was added to the top compartment of a modified Boyden chamber; and the inhibitor also reduced the MMP secretion and PMA-induced in vitro invasion in various glioma cell lines. Conclusions. These results indicate that activation of p38 MAPK by PMA plays a central role in the regulation of MMPs and TIMPs in D54 cells, which has a major influence in tumor invasion and metastasis. Furthermore, inhibition of p38 MAPK by SB203580 blocked the secretion of MMPs and in vitro invasion of various glioma cells, underscoring a possible role of p38 MAPK inhibitors as antiinvasive and/or antimetastatic agents of malignant gliomas.

Effects of dexamethasone and methylprednisolone on cell cultures of human glioblastomas

1971 ◽  
Vol 34 (3) ◽  
pp. 324-334 ◽  
Author(s):  
John Mealey ◽  
Tsu T. Chen ◽  
George P. Schanz
Keyword(s):  
Cell Cultures ◽  
Glioma Cells ◽  
Clinical Applications ◽  
Natural Rate ◽  
Content Type ◽  
Culture Growth ◽  
Different Origins ◽  
Dose Dependent ◽  
Fine Print

✓ Eight biopsied glioblastomas were propagated in vitro through multiple, serial cell cultures which were exposed to dexamethasone and methylprednisolone in concentrations ranging from 0.25 to 400 µg/ml. The higher concentrations of both steroids produced inhibition of culture growth and cytotoxic damage which appeared relatively nonspecific. Although the responses observed were dose-dependent, the sensitivity among glioma cultures of different origins varied. Of the two steroids, Methylprednisolone was more injurious to glioma cells in vitro and was cytolytic in doses of 400 µg/ml. Growth inhibition was demonstrated after a 1-day exposure to this corticoid, but this effect was usually transient at lower doses. Thereafter, surviving resistant cells resumed their natural rate of growth in the continued presence of the steroid as well as under standard conditions of culture. Potential clinical applications of the antineoplastic properties of corticosteroids against the gliomas are discussed, emphasizing the need to investigate additional, possibly more efficacious compounds.

Enhancement of macrophage cytotoxicity against murine gliomas by interferon beta increase in nitric oxide production in response to glioma-derived soluble factors

2002 ◽  
Vol 97 (3) ◽  
pp. 619-626 ◽  
Author(s):  
Tomohiro Kito ◽  
Etsushi Kuroda ◽  
Akira Yokota ◽  
Uki Yamashita
Keyword(s):  
Nitric Oxide ◽  
Cytotoxic Activity ◽  
Glioma Cells ◽  
Cell Contact ◽  
No Production ◽  
Soluble Factors ◽  
Content Type ◽  
Culture Supernatants ◽  
Fine Print

Object. In previous studies interferon-β (IFNβ) has been shown to suppress tumor growth. In this report, the antitumor effect of macrophages stimulated with IFNβ is investigated in murine gliomas in vitro. Methods. The authors examined the cytotoxic activity of IFNβ-stimulated peritoneal macrophages in glioma cells labeled with [3H]thymidine. The addition of IFNβ enhanced cytotoxic activity in gliomas as well as the nitric oxide (NO) production of macrophages in cocultures. Addition of NG-monomethyl-l-arginine (l-NMMA) and l-N6-(1-iminoethyl)-lysine, but not d-NMMA (an inactive analog of l-NMMA), blocked this cytotoxic activity. The addition of IFNβ had no direct effect on the growth of glioma cells. Because NO was not produced from macrophages treated with IFNβ alone and IFNβ-induced cytotoxic activity did not need cell-to-cell contact, the authors suspected that gliomas produce some soluble factors that act as cofactors for IFNβ-induced cytotoxic activity. Macrophages stimulated with IFNβ in the presence of glioma culture supernatants showed higher cytotoxicity against glioma cells than macrophages stimulated with IFNβ alone. Furthermore, NO was markedly produced by IFNβ-stimulated macrophages in the presence of glial culture supernatants. Conclusions. These data indicate that the antiglioma activity of IFNβ through macrophages is due to NO produced by macrophages and that glioma-derived soluble factors play a role as an essential cofactor in this activity.

Survival times and case fatality rates of brain-injured persons

1985 ◽  
Vol 63 (4) ◽  
pp. 537-543 ◽  
Author(s):  
Jess Kraus ◽  
Carol Conroy ◽  
Pamela Cox ◽  
Karen Ramstein ◽  
Daniel Fife
Keyword(s):  
Survival Time ◽  
Injury Severity ◽  
Case Fatality ◽  
Survival Times ◽  
Medical Assistance ◽  
Content Type ◽  
Intracranial Surgery ◽  
Brain Injured ◽  
Time From Injury ◽  
Fine Print

✓ Survival time after injury (the time from injury to death) imposes an important constraint on the timing of the delivery of postinjury medical care. From a population-based study of brain-injured people, the survival times in 542 cases with fatal outcomes were studied. Prehospital deaths as well as hospital deaths were included. Survival times were considerably shorter for 95 people with untreatable injuries (Abbreviated Injury Scale level 6) than for the remaining 447 whose injuries were potentially treatable. For the former group, the median survival time was 10 minutes; for the latter, it was 2 hours. For those with potentially treatable injuries, the median time from injury to receiving medical assistance was approximately 30 minutes and 82% received medical assistance within 1 hour of injury. Short survival time was associated with prehospital death, young age, high Injury Severity Score, and having a nonbrain injury as the most severe injury. For patients who arrived alive at a hospital, intracranial surgery was associated with increased survival time.

Statistical analysis of clinicopathological features, radiotherapy, and survival in 170 cases of oligodendroglioma

1987 ◽  
Vol 67 (2) ◽  
pp. 224-230 ◽  
Author(s):  
Karl-Fredrik Lindegaard ◽  
Sverre J. Mørk ◽  
Geir E. Eide ◽  
Tore B. Halvorsen ◽  
Reidulv Hatlevoll ◽  
...  
Keyword(s):  
Survival Time ◽  
Median Survival ◽  
Postoperative Radiotherapy ◽  
Survival Rates ◽  
Tumor Resection ◽  
Survival Times ◽  
Term Survival ◽  
Content Type ◽  
Postoperative Irradiation

✓ The postoperative survival time of 170 nonrandomized patients treated for cerebral oligodendrogliomas in Norway from 1953 to 1977 was studied. Survival times were significantly prolonged if postoperative irradiation was performed in addition to surgery (median survival time 26.5 vs. 38 months, p = 0.039). In the group without postoperative radiotherapy, the 5-year rate of survival was 27% compared with 36% in the irradiated patients. The respective survival rates after 8 years were 14% versus 17%; thus, there was little effect on long-term survival. Irradiation appears not to be of benefit after “total” removal. Patients with partly resected lesions appeared to benefit from postoperative radiotherapy; the median survival period after subtotal tumor resection was 37 months with and 26 months without radiotherapy (p = 0.0089). The findings also indicate that irradiation doses between 40 and 50 Gy were as effective as doses between 50 and 60 Gy in increasing the patients' probability of surviving 5 years after subtotal tumor resection. Since the risk of radiation necrosis is proportional to the dose applied, the lower dose is recommended. These conclusions were also valid when adjustments were made for prognostically significant histological and clinical features.

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